1/5/2015

Biomedical Research Models, Inc.

Contract Discovery and Preclinical Research

Alzheimer’s Disease

1/5/2015

Clinical Symptoms of AD

• Memory loss that disrupts daily

life

• Changes in planning of solving

problems

• Difficulty completing familiar

tasks at home, at work or at

leisure

• Confusion with time or place

• Trouble understanding visual

images and spatial relationships

• New problems with words in

speaking or writing

• Misplacing things and losing the

ability to retrace steps

• Decreased or poor judgment

• Withdrawal from work or social

activities

• Changes in mood and

personality

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Risk Factors of AD

• Age

• Genetics

• Insulin resistance

• Hyperglycemia

• Inflammation

• Oxidative stress

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7 Stages of Alzheimer’s

Disease

7 Stages of AD

• 1 – no impairment

• 2 – very mild decline

• 3 – mild decline

• 4 – moderate decline (mild to early stage)

• 5 – moderately server decline (moderate to mid-stage)

• 6 – sever decline (moderately severe to mid-stage)

• 7 – very severe decline (severe or late state)

1/5/2015

Comparison between BB/Wor-

and BBZDR/Wor-Diabetic Rats

1. Neuronal loss

2. Neuronal apoptosis

3. Alterations of various factors mediating apoptotic

activity:

- Apoptosis-regulating proteins

- Perturbation of IGF system

- Activation of Fas/NGF-R.p75

- Oxidative stress: PARP, 8-OHdG

- Caspase activation

1/5/2015

CA1

CA2

CA3

CA4

DFSub

Neuronal densities in type 1 vs. type 2

diabetic BB/Wor ratsN

euro

nal

den

sity

(n

um

ber

s/m

m2)

0

500

1000

1500

2000

2500

3000

3500

CA1 CA2 CA3 CA4

*** ** †

* p < 0.05, *** p < 0.001 vs. control, † p < 0.05 vs. BB/Wor

Control (n=4)

BBZDR/Wor (n=4)

BB/Wor (n=4)

1/5/2015

a). Active caspase-3

*

0

1.0

2.0

3.0

Control BB/Wor BBZDR

15 kD

22 kD

-17 kD

b). Caspase 12

0

1.0

2.0

3.0

4.0 *

†

Control BB/Wor BBZDR

51 kD

62 kD-55 kD

Rel

ati

ve

den

sity

(A

rbit

ral

un

it)

Rel

ati

ve

den

sity

(A

rbit

ral

un

it)

* p < 0.05 vs. control; † p < 0.05 vs. BB/Wor

Expression of caspases in type 1 vs.

type 2 diabetic BB/Wor rats

1/5/2015* p < 0.05, ** p < 0.01 vs. control. † p < 0.05 vs. BB/Wor

Bax

Control BB/Wor BBZDR /Wor

Bcl-xL

Control BB/Wor BBZDR/Wor

0

1.0

2.0

3.0

**

†

0

0.5

1.0

1.5

Rel

ati

ve

den

sity

(Arb

itra

lu

nit

)

Apoptosis- regulating proteins in type 1 vs.

type 2 diabetic BB/Wor rats

(hippocampus, 8 months)

1/5/2015

Splicing of the transmembranous

APP-molecule

APP

Cell-membrane

-secretase-secretase

I-40 AS

(vessels)

I-42 AS

(neurons)

1/5/2015

APP Frontal Cortex

Control

BB/W

BB/ZDR Cont BB/W BB/Z

0.0

1.0

2.0

3.0**

**

** p < 0.005 vs. control

1/5/2015

β – Secretase Frontal Cortex

Control

BB/W

BB/ZDRCont BB/W BB/Z

0.0

1.0

2.0 ***

* p < 0.05, ** p < 0.005 vs. control

1/5/2015

Control

BBW

BBZ

Aβ 1-42 Frontal Cortex

Cont BB/W BB/Z

***

*

0.0

2.0

3.0

1.0

2.0

* p < 0.05, ** p < 0.005 vs. control

1/5/2015

Formation of Paired Helical

Filaments (NFT)

β-amyloid

Adap78

Calcineurin

Hyperphosphorylated Tau

Caspase 3 Spliced Tau

; β

Enmark and Davis, 2002

APOPTOSIS

Apoptosis

inducing

elements

Cell death

1/5/2015

References

• Li ZG., Zhang W., Sima AA. Alzheimer-like

changes in rat models of spontaneous diabetes.

Diabetes 2007 Oct;56(10):2650.

• Sima AA. Encephalopathies: the emerging

diabetic complications. Acta Diabetologica

August 2010.

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